The Lung From a Pharmacology Perspective

Question 1

What receptors do drugs that act on the autonomic nervous system to prevent bronchospasm act on?
• is the PNS or SNS dominant? why?

Answer 1

• ß2-adrenergic agonists
• Muscarinic Antagonists

• PNS is dominant in the respiratory tract because it contains receptors that act directly on the bronchial smooth muscle. SNS drugs do not.

Question 2

What cells do the adrenergic receptors in the lung act on?

Answer 2

• Epithelial Cells
• Mast Cells
• Type II alveolar Cells

Question 3

M1 Receptors:
• where are they located?
• What do they do?

Answer 3

Location:
• M1 receptors are located on the POST-GANGLIONIC membrane to transduce vagal signal to BOTH:
1. Submucosal Glands
2. Airway Smooth muscle

***M1’s are also responsible for increased glandular secretions in the nasal mucosa

Question 4

M2 Receptors:
• Where are they located?
• What do they do?

Answer 4

Location:
• M2’s are INHIBITORY Autoreceptors on the PRE-SYNAPTIC membrane of POST-GANGLIONIC FIBERS

• ALSO are found on AIRWAY SMOOTH MUSCLE where they oppose the increase in c-AMP caused by ß2 adrenergic stimulation

Question 5

M3 Receptors:
• Where are they located?
• What do they do?

Answer 5

Location:
• Bronchial smooth muscle - Bronchoconstriction

•Submucosal Glands - Mucus secretion

Question 6

What would be the consequence of administering a drug that antagonizes both M2 and M3 receptors?
• Name two drugs that do this.

Answer 6

M2 antagonism:
• tends to enhance PNS effects because there is no off signal with the Ach M2 heteroreceptor
• would help to relax tense bronchi

M3 antagonism:
• tends to attenuate PNS effects because it turns off mucous secretion and smooth muscle contraction

2 drugs:
•Atropine
• Ipratropium

Question 7

What muscarinic antagonist blocks M1 and M3 receptors equally well?

Answer 7

Tiotropium

Question 8

What are some 1st generation Antihistamines that may cause drying of secretions in the lungs?

Answer 8

• Chlorpheniramine
• Doxylamine
• Diphenhydramine

Question 9

What effect would acetylcholinesterase inhibitors have on the lungs? Why?
• Name two.

Answer 9

• Edrophonium
• Neostigmine

=> treat myasthenia gravis

Question 10

At what stage in the bronchospastic response should SNS drugs be given?
• do these drugs antagonize or agonize receptors?

Answer 10

SNS drugs:
• AGONISTS should be given EARLY in the bronchospastic response otherwise they wont be effective

• Albuterol is the example of such a drug

Question 11

What is the risk of taking a ß2 agonist?

Answer 11

• May produce bronchoconstriction by increasing the PNS tone

Question 12

What is the effect of ß2 stimulation on:
• Mast Cells
• Mucociliary Clearance
• Vascular Endothelial Permeability

Answer 12

Mast Cells:
• Reduces Histamine Secretion

Mucociliary Clearance:
• Increase Glycoprotein
• Increase beat frequency of Cilia

Vascular Endothelial Permeability:
• DECREASES Leakage from microvasculature

Question 13

What is the risk of giving ultra high concentrations of a ß2 agonist?

Answer 13

• CV stimulatory effects
• Prolongation of the QT interval especially in presence of HYPOKALEMIA
• Widening of Pulse Pressure
• DIlation in coronary, pulmonary, and skeletal mm.

Question 14

How could a ß2 agonist aggravate pre-existing hypokalemia?

Answer 14

• Stimulation of Na+/K+ ATPase in skeletal mm.
• Increased intracellular K+
• Decreased serum K+

*this is why you should avoid giving these with other drugs that cause hypokalemia

Question 15

What is responsible for the tremor experienced when taking ß2 agonists?

Answer 15

Stimulation of Na+/K+ ATPase activity is responsible for the twitching and tremor seen in people who use these

Question 16

What are the 5 groups of drugs that you should worry about interacting in someone who is taking a ß2-agonist?

Answer 16

• Tricyclic Antidepressants (TCAs)
• Monoamine Oxidase Inhibitors (MAOIs)
• Saquinavir (HIV drug)
• Loop and Thiazide Diuretics
• Non-specific ß2-blockers

Question 17

Name two TCAs and explain why they interact with ß2-agonists.

Answer 17

• Amitriptyline and Desipramine

* Block Reuptake of drug and Norepinephrine into nerve terminal

Question 18

Name two Monoamine oxidase inhibitors and explain why they interact with ß2-agonists.

Answer 18

Selegilene and Rasagilene

• Block Metabolism of amine by Monamine Oxidase-B

Question 19

Explain why Saquinavir (HIV drug) interacts with ß2-agonists.

Answer 19

• Promotes Hypokalemia
• QT prolongation
• Arrythmias

Question 20

Explain why loop and Thiazide Diuretics interact with ß2-agonists.

Answer 20

Predispose patient to hypokalemia and INCREASE the likelihood of QT prolongation/arrythmias

• Monitor serum K+ in these ppl.

Question 21

Why type of GPCR are M1 and M3 receptors?

• M2?

Answer 21

• Gq stimulatory receptors = M1/M3

* Gi/o receptors = M2

Question 22

Why does overusing an inhaler lead to a loss in potency?

• explain this process.

Answer 22

Internalization of Receptors
• Repeated stimulation => C-terminus phosphorylization of receptor via PKA or ß-adrenergic receptor Kinase (ßARK).
• ß-arrestin binds to phosphorylated domain and blocks Gs binding
• Decrease in Adenylyl Cyclase activity

Genes may also be affected on a long term basis

Question 23

Why would you give a patient with asthma that doesn’t respond well to albuterol corticosteroids?

Answer 23

Corticosteroids upregulate ß2 receptor transcription

Question 24

Compare lung permeability to macromolecules and small molecules compared to other portals?

Answer 24

Macromolecules:
• Far more permeable than any other portal

Small Molecules:
• More permeable than small to the GI tract

Question 25

T or F: small molecules are delivered cleanly via the lung and produce very few metabolite.

Answer 25

True

Question 26

T or F: no non-invasive route can deliver a drug at the same speed that the respiratory tract can.

Answer 26

True

Question 27

What opportunistic oral flora might arise in someone who is using an inhaler frequently?
• how can this be attenuated?

Answer 27

• Candidiasis - locally suppressed immune function by corticosteroids allows for it to flourish
• Washing your mouth out after administration or using a spacer device could help with this

Question 28

What is the problem with acidic powders that are delivered via inhaler?
• how can this be attenuated?

Answer 28

• They may corrode your teeth

* Washing your mouth out after administration or using a spacer device could help with this

Question 29

Will drugs that are deposited on the tracheal epithelial surface be absorbed quickly?

Answer 29

NO - tracheal thickness = 50-60µm whereas alveolar thickness is around 0.2µm

Question 30

Would you expect a hydrophobic or hydrophilic drug to be absorbed more rapidly via the respiratory route?

Answer 30

• Lipid Soluble Drugs are absorbed more rapidly because they can diffuse across the epithelium
• Water soluble drugs are likely absorbed paracellularly in which they pass through aqueous pores in the intercelular tight junctions

Question 31

What is the most important physicochemical property that determines if a small drug can cross the lung epithelium?

Answer 31

• Ionization is the main determinant for molecules between 100 and 1000 D

Question 32

What 4 general groups of drugs work in the upper respiratory tract?

Answer 32

1. Mucolytics
2. Vasoconstrictors -> alpha-1 agonists
3. Drugs acting in the CNS cough center
4. Antihistamines

Question 33

What are the 2 general kinds of drugs used to treat COPD and Restrictive lung diseases?
• what are some drugs types that fall into these categories?

Answer 33

1. Bronchodilators
   • Anticholinergic
   • Adrenergics
   • Adenosine antagonist
2. Anti-inflammatory
   • Corticosteroids
   • LTAs
   • Adenosine antagoists

Question 34

What drugs are used in the the treatment of Pulmonary Artery Hypertension?

Answer 34

• Prostanoids
• Endothelin Antagonists
• PDE-5 inhibitors

Question 35

What drugs are used in the treatment of Cystic Fibrosis?

Answer 35

CTFR potentiators (ivacaftor)